A turning point in adjuvant therapy: Optimizing use of aromatase inhibitors P Pronzato Genova

A turning point in adjuvant A turning point in adjuvant therapy:therapy:Optimizing use of aromatase Optimizing use of aromatase inhibitorsinhibitors

P PronzatoP Pronzato

GenovaGenova

Invasive Breast Cancer by Age Invasive Breast Cancer by Age and ER-PR status. (Year 1998)and ER-PR status. (Year 1998)

0

10

20

30

40

50

60

70

20-39 40-49 50-59 60-69 70-79 80+

Perc

en

tag

e

ER-/PR- ER+/PR+ Other

Li CL et al. J Clin Oncol 2003, 1:28

Mortalità per cancro negli ultimi 50 Mortalità per cancro negli ultimi 50 annianni

EBCTCG, Lancet 2005

Anastrozole or Letrozole or Exemestane

Tam +/-LHRHa or AI

+ LHRHa

UPFRONT or

SWITCH How long?

Tam +/-LHRHa or AI

+ LHRHa

UPFRONT or

SWITCH How long?

Anastrozole or Letrozole or Exemestane

OptimizationOptimization

Premenopause (+ LHRHa)Premenopause (+ LHRHa) Upfront vs early switchUpfront vs early switch Duration after switchDuration after switch Which AIWhich AI Selection of ptsSelection of pts

Tumor characteristicsTumor characteristics Pt CharacteristicsPt Characteristics

The Intergroup Exemestane The Intergroup Exemestane Study (IES): Mature AnalysisStudy (IES): Mature Analysis

0 20 40 60 80 100 120 140 160

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Pro

bab

ility

of

Ove

rall

Su

rviv

al

WeeksOS, overall survival.

Kaufmann, et al. J Clin Oncol. 2000;18:1399-1411.

All end points, including OS, successfully acheived All end points, including OS, successfully acheived in advanced breast cancer in advanced breast cancer

Exemestane Is Effective Exemestane Is Effective After Prior TamoxifenAfter Prior Tamoxifen

Exemestane

P-value

0.039

E

Not Reached

M

123.4 weeks

Megestrol acetateMedian survivalMedian survival

Exemestane as Initial Therapy for MBC: Randomized Exemestane as Initial Therapy for MBC: Randomized EORTC Phase II/III TrialEORTC Phase II/III Trial

ExemestaneExemestane TamoxifenTamoxifen

PFS mediana PFS mediana (mesi)(mesi)

9.9 9.9 5.85.8

% PFS a 6 % PFS a 6 mesimesi

66%66% 49%49%

% PFS a 12 % PFS a 12 mesimesi

42%42% 31%31%

Risposte Risposte ObiettiveObiettive

46%46% 31%31%

Clinical Clinical BenefitBenefit

66%66% 49%49%

R Paridaens, ASCO 2004R Paridaens, ASCO 2004

10-Year Follow-up: Long-Term Efficacy 10-Year Follow-up: Long-Term Efficacy of of ~2 Years of Adjuvant Tamoxifen~2 Years of Adjuvant Tamoxifen

Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;351:1451-1467.

00 10+10+55

4040

2020

00

8080

6060

100100

ControlControl

TamoxifenTamoxifen~ 2 years~ 2 years

ControlControl


YearsYears

Node -Node -

Node +Node +

Node – : 2.3% Node – : 2.3% SDSD 1.3: 2p = 0.06 1.3: 2p = 0.06Node + : 7.2% Node + : 7.2% SDSD 1.2: 2p < 0.00001 1.2: 2p < 0.00001

69.7%69.7%

48.2%48.2%

74.3%74.3%

55.4%55.4%

88.9%88.9%

76.8%76.8%

90.6%90.6%

79.0%79.0%

00 10+10+55

4040

2020

00

8080

6060

100100

ControlControl


ControlControl


(%)

(%)

YearsYears

Node -Node -

Node +Node +

Node – : 5.6% Node – : 5.6% SDSD 1.3: 2p < 0.00001 1.3: 2p < 0.00001Node + : 10.0% Node + : 10.0% SDSD 1.2: 2p < 0.00001 1.2: 2p < 0.00001

51.4%51.4%

39.5%39.5%

63.5%63.5%

49.5%49.5%

81.4%81.4%

72.6%72.6%

87.1%87.1%

78.2%78.2%

Recurrence as Recurrence as first eventfirst event

MortalityMortality

(%)

(%)

Results of the Results of the Intergroup Exemestane Study (IES)Intergroup Exemestane Study (IES)

TAMOXIFENTAMOXIFEN

ExemestaneExemestane(n=2352)(n=2352)

TamoxifenTamoxifen(n=2372)(n=2372)

RRAANNDDOOMMI I ZZEE

Post Post Treatment Treatment Follow-upFollow-up

2-3 years2-3 years study

treatment

Diagnosis Start of study

Total 5 years endocrine therapy

IES Trial DesignIES Trial Design

Coombes, ASCO 2006.

• 56 months median follow-up 56 months median follow-up • Over 99% of patients have completed treatmentOver 99% of patients have completed treatment

More than 2 years of post-treatment

follow-up

IES: The Pivotal Study of Switching IES: The Pivotal Study of Switching Adjuvant Therapy in Breast CancerAdjuvant Therapy in Breast Cancer

• Double-blind, prospective randomized trialDouble-blind, prospective randomized trial

• 4724 patients*4724 patients*

• 20 cooperative groups 20 cooperative groups

• 37 countries37 countries

• 366 centers366 centers

Coombes, ASCO 2006.

*Intent-to-treat (ITT) population

IES Eligibility CriteriaIES Eligibility Criteria

• Key inclusion criteria:Key inclusion criteria:– 2 to 3 years of adjuvant tamoxifen therapy2 to 3 years of adjuvant tamoxifen therapy– ER-positive or unknown breast cancerER-positive or unknown breast cancer– Confirmed postmenopausal statusConfirmed postmenopausal status– Previous chemotherapy permittedPrevious chemotherapy permitted

• Key exclusion criteria:Key exclusion criteria:– Known ER-negative statusKnown ER-negative status– Clinical evidence of local relapse or distant Clinical evidence of local relapse or distant

metastasesmetastases– Osteoporosis and/or osteoporotic fracturesOsteoporosis and/or osteoporotic fractures

Coombes, ASCO 2006.

IES Study End PointsIES Study End Points

Primary end point:Primary end point: • Disease-free survival (DFS), Disease-free survival (DFS), defined as:defined as:

• Breast cancer recurrence (local or distant)Breast cancer recurrence (local or distant)• Contralateral breast cancerContralateral breast cancer• Death from any cause Death from any cause

Secondary end points:Secondary end points:• Overall survival (OS)Overall survival (OS)• Contralateral breast cancerContralateral breast cancer• Long-term tolerability and safety Long-term tolerability and safety

Additional end points:Additional end points:• Breast Cancer Free Survival (BCFS)Breast Cancer Free Survival (BCFS)• Time To Distant Recurrence (TTDR)Time To Distant Recurrence (TTDR)

Coombes, ASCO 2006.

IES Patient Demographics IES Patient Demographics ExemestaneExemestane

(n=2352)(n=2352)

TamoxifenTamoxifen

(n=2372)(n=2372)

Median Age - years, n (range)Median Age - years, n (range) 63.9 (38.2 – 96.1)63.9 (38.2 – 96.1) 63.8 (31.7 – 90.6)63.8 (31.7 – 90.6)

Nodal StatusNodal Status

NegativeNegative 51.7 %51.7 % 51.9 %51.9 %

PositivePositive 44.6 %44.6 % 43.8 %43.8 %

Missing/UnknownMissing/Unknown 3.7 %3.7 % 4.3 %4.3 %

Prior ChemotherapyPrior Chemotherapy

YesYes 32.9 %32.9 % 32.4 %32.4 %

NoNo 67.1 %67.1 % 67.6 %67.6 %

Receptor StatusReceptor Status

ER + & PR +ER + & PR + 57.0 %57.0 % 56.0 %56.0 %

ER + & PR - / UnknownER + & PR - / Unknown 29.0 %29.0 % 29.2 %29.2 %

ER & PR Unknown ER & PR Unknown 11.7 %11.7 % 12.0 %12.0 %

ER - ER - 2.4 %2.4 % 2.8 %2.8 %

Coombes, ASCO 2006.

Efficacy in the Intergroup Efficacy in the Intergroup Exemestane Study (IES) Exemestane Study (IES)

Does Exemestane Improve Does Exemestane Improve Disease-Free Survival?Disease-Free Survival?

En

d o

ftreatm

ent

0

10

2030

40

50

60

7080

90

100

0 1 2 3 4 5

Time since randomization (years)

% s

urv

ivin

g d

isease f

ree

Intent to Treat

HR = 0.76HR = 0.76

95% CI (0.66 – 0.88)95% CI (0.66 – 0.88)

PP-value-value 0.00010.0001

354 events2352 at risk


Coombes, ASCO 2006.

Exemestane

Tamoxifen

2.5 years2.5 years

3.2 (1.6 – 4.9)3.2 (1.6 – 4.9)

5 years5 years

3.4 (0.1 – 6.8)3.4 (0.1 – 6.8)% absolute difference (95% CI)% absolute difference (95% CI)

Does Exemestane ImproveDoes Exemestane ImproveDisease-Free Survival?Disease-Free Survival?

HR = 0.75HR = 0.75

95% CI (0.65 – 0.87)95% CI (0.65 – 0.87)


En

d o

ftreatm

ent

0

10

20

30

4050

60

70

80

90

100

0 1 2 3 4 5


% s

urv

ivin

g d

isease f

ree

ER+/Unknown Patients

Coombes, ASCO 2006.


Exemestane

Tamoxifen438 events2306 at risk

2.5 years2.5 years

3.4 (1.8 – 5.1)3.4 (1.8 – 5.1)

5 years5 years

3.5 (0.1 – 6.9)3.5 (0.1 – 6.9)% absolute difference (95% CI)% absolute difference (95% CI)

Does Exemestane Improve Does Exemestane Improve Disease-Free Survival? Disease-Free Survival?

En

d o

ftreatm

ent

0.00

0.05

0.10

0.15

0.20

0.25

0 1 2 3 4 5


Cu

mu

lati

ve R

ate

Coombes, ASCO 2006.

Annual Hazard Rate, % (95% CI)Annual Hazard Rate, % (95% CI)

ExemestaneExemestane 2.5 (1.9, 3.2)2.5 (1.9, 3.2) 3.0 (2.3, 3.8)3.0 (2.3, 3.8) 4.1 (3.3, 5.0)4.1 (3.3, 5.0) 4.0 (3.1, 5.0)4.0 (3.1, 5.0) 4.4 (3.4, 5.9)4.4 (3.4, 5.9)

TamoxifenTamoxifen 3.6 (2.9, 4.4)3.6 (2.9, 4.4) 4.7 (3.9, 5.8)4.7 (3.9, 5.8) 5.0 (4.1, 6.1)5.0 (4.1, 6.1) 4.2 (3.3, 5.3)4.2 (3.3, 5.3) 4.6 (3.4, 6.0)4.6 (3.4, 6.0)



Exemestane

Tamoxifen

Intent to Treat, Cumulative Hazard Rate

En

d o

ftreatm

ent

ER+/Unknown, Cumulative Hazard Rate

Exemestane



Does Exemestane ImproveDoes Exemestane ImproveDisease-Free Survival? Disease-Free Survival?

Coombes, ASCO 2006.

0.00

0.05

0.10

0.15

0.20

0.25

0 1 2 3 4 5


Cu

mu

lati

ve R

ate

Does Exemestane Reduce First Events?Does Exemestane Reduce First Events?

Coombes, ASCO 2006.

0

50

100

150

200

250

300

Nu

mb

er o

f F

irst

Eve

nts

Local Local RecurrenceRecurrence

Contralateral Contralateral Breast CancerBreast Cancer

Distant Distant RecurrenceRecurrence

TamoxifenTamoxifenExemestaneExemestane

Intercurrent Intercurrent DeathsDeaths

6868

256256

214214

35351818

95957373

4949

Is Exemestane Consistent Across Is Exemestane Consistent Across Subgroups for DFS?Subgroups for DFS?

0.74 (0.58, 0.95)0.71 (0.59, 0.84)

0.74 (0.62, 0.89)0.76 (0.61, 0.95)

0.75 (0.64, 0.87)0.79 (0.55, 1.14)

0.76 (0.63, 0.92)0.74 (0.60, 0.92)

0.79 (0.61, 1.03)0.68 (0.54, 0.85)0.83 (0.64, 1.07)

0.74 (0.64, 0.85)

Coombes, ASCO 2006.CT, chemotherapy; *Adjusted for nodal status, chemotherapy use, & HRT use.

Hazard ratio (95% CI)0.5 0.6 0.8 1.0 1.2

DFS (Adjusted)*

Age >70 yrs (1153) Age 60-69 yrs (1969)

Age <60 yrs (1480)

Prior tam >2.5 yrs (1838) Prior tam <=2.5 yrs (2764)

ER unknown (560) ER positive (4042)

Previous CT (1499) No previous CT (3103)

Nodes positive (2038) Nodes negative (2384)

P<0.0001

HR (95% CI)

Favors TamoxifenFavors Exemestane

ER+/UnknownER+/Unknown

How Does Exemestane Impact How Does Exemestane Impact Different Efficacy End Points?Different Efficacy End Points?


Hazard ratio (95% CI)

ITT (E=20, T=35)

Time to Contralateral BC

ER+/UNK (E=238, T=285)

Time to Distant Recurrence

Breast Cancer-Free Survival

Disease-Free Survival

0.4 0.6 0.8 1.0 1.2

ER+/UNK (E=20, T=35)

ITT (E=249, T=297)

ITT (E=354, T=454)

ITT (E=289, T=374)

ER+/UNK (E=277, T=361)

ER+/UNK (E=339, T=438) 0.75 (0.65, 0.87)

0.75 (0.64, 0.87)

0.82 (0.69, 0.98)

0.56 (0.33, 0.98)

0.76 (0.66, 0.88)

0.76 (0.65, 0.88)

0.83 (0.70, 0.98)

0.57 (0.33, 0.98)

Coombes, ASCO 2006.

HR (95% CI)

Does Exemestane Improve Does Exemestane Improve Overall Survival?Overall Survival?

En

d o

ftreatm

ent

0

10

20

30

4050

60

70

80

90

100

0 1 2 3 4 5


Wo

men

ali

ve (

%)

Coombes, ASCO 2006.

HR = 0.85HR = 0.85

95% CI (0.71 – 1.02)95% CI (0.71 – 1.02)

PP value value 0.080.08


Exemestane


Tamoxifen

2.5 years2.5 years

0.8 (-0.4 – 1.9)0.8 (-0.4 – 1.9)

5 years5 years

1.2 (-1.5 – 3.9)1.2 (-1.5 – 3.9)% absolute difference (95% CI)% absolute difference (95% CI)

Intent to Treat


En

d o

ftreatm

ent

0

1020

3040

50

6070

8090

100

0 1 2 3 4 5


Wo

men

ali

ve (

%)

HR = 0.83HR = 0.83

95% CI (0.69 – 1.00)95% CI (0.69 – 1.00)


Coombes, ASCO 2006.

ER+/Unknown

2.5 years2.5 years

0.7 (-0.4 – 1.9)0.7 (-0.4 – 1.9)

5 years5 years

1.6 (-1.2 – 4.3)1.6 (-1.2 – 4.3)% absolute difference (95% CI)% absolute difference (95% CI)


Exemestane


Tamoxifen


En

d o

ftreatm

ent

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0 1 2 3 4 5


Cu

mu

lati

ve R

ate

Coombes, ASCO 2006.

Annual Hazard Rate, % (95% CI)Annual Hazard Rate, % (95% CI)

ExemestaneExemestane 0.8 (0.5, 1.2)0.8 (0.5, 1.2) 1.8 (1.3, 2.5)1.8 (1.3, 2.5) 2.2 (1.6, 2.9)2.2 (1.6, 2.9) 3.6 (2.8, 4.5)3.6 (2.8, 4.5) 2.3 (1.6, 3.4)2.3 (1.6, 3.4)

TamoxifenTamoxifen 1.0 (0.7, 1.5)1.0 (0.7, 1.5) 2.4 (1.8, 3.1)2.4 (1.8, 3.1) 2.5 (2.0, 3.3)2.5 (2.0, 3.3) 3.2 (2.5, 4.1)3.2 (2.5, 4.1) 2.9 (2.1, 4.1)2.9 (2.1, 4.1)

Exemestane222 events2352 at risk


Intent to Treat, Cumulative Hazard Rate


Coombes, ASCO 2006.

En

d o

ftreatm

ent

ER+/Unknown, Cumulative Hazard Rate


Exemestane


Tamoxifen

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0 1 2 3 4 5


Cu

mu

lati

ve R

ate

IES Efficacy SummaryIES Efficacy Summary**

• Death: 17% (Death: 17% (PP=0.05)=0.05)17% (17% (PP=0.04), adjusted=0.04), adjusted

• Recurrence and deaths: 25% (Recurrence and deaths: 25% (PP=0.0001)=0.0001)

• Contralateral breast cancer: 44% (95% CI, 0.33-0.98)Contralateral breast cancer: 44% (95% CI, 0.33-0.98)

• Distant recurrence: 18% (95% CI, 0.69-0.98)Distant recurrence: 18% (95% CI, 0.69-0.98)

Switching to exemestane reduces the risk of:Switching to exemestane reduces the risk of:

Coombes, ASCO 2006.

*Note: ER+/Unknown patients.

Safety and Tolerability in the Safety and Tolerability in the Intergroup Exemestane Study (IES)Intergroup Exemestane Study (IES)

Cardiovascular and Thromboembolic Cardiovascular and Thromboembolic Adverse EventsAdverse Events

22.1% v 20.9%

1.8% v 1.8%

1.0% v 0.8%

2.5% v 2.4%

1.9% v 3.1%*

0.1% v 0.1%

9.9% v 8.6%1.3% v 0.8%

11.3% v 11.2%

Exemestane v Tamoxifen


Odds Ratio (99% CI)

Thromboembolic

Other cardiac

Sudden death

CVA

Peripheral Vascular Disease

Heart failure

Angina MI

Ischemic cardiac

All CV/TE

0.4 0.6 0.8 1.0 1.2 1.82.0

7.1% v 6.5%

Coombes, ASCO 2006.

*P=0.01.

9.2% v 7.2%*

Musculoskeletal and Other Musculoskeletal and Other Adverse EventsAdverse Events

17.5% v 14.6%†

7.0% v 4.9%†

0.6% v 0.4%0.6% v 0.2%1.1% v 1.3%5.0% v 3.4%†

25.7% v 20.3%†

20.8% v 15.1%†

2.0% v 1.1%*2.5% v 4.4%†

1.2% v 0.3%†

2.8% v 0.4%†


Odds Ratio (99% CI)

Musculoskeletal pain

Carpal tunnel

Gastric ulcer

Muscle cramps Joint stiffness

Arthralgia

Arthritis (All types) Osteoporosis

Other Wrist Spine

Hip Fracture

0.4 0.8 1.0 2.0 3.0 4.0 6.0 8.00.6

Coombes, ASCO 2006.


*P≤0.01; †P≤0.001.

Gynecologic Adverse EventsGynecologic Adverse Events


6.4% v 9.8%*

Odds Ratio (99% CI)

Endometrial cancer

Uterine D&C‡

Hysterectomy

Uterine polyps/fibroids

Endometrial hyperplasia

Vaginal bleeding

Serious gynecologic

0.1 0.2 0.4 0.6 0.8 1.01.2

Coombes, ASCO 2006.

4.8% v 7.1%*

0.2% v 1.0%*

1.4% v 4.0%*

0.9% v 1.5%

0.7% v 1.5%†

0.4% v 0.7%


*P≤0.001; †P=0.006; ‡dilation and curettage.

Sites of Other Invasive CancersSites of Other Invasive Cancers

ExemestaneExemestane TamoxifenTamoxifen

UterusUterus 99 1717

GIGI 1818 2828

LungLung 99 1515

MelanomaMelanoma 44 55

OvaryOvary 66 44

OtherOther 2626 3838

Total Non-Breast Second PrimariesTotal Non-Breast Second Primaries 7272 107107

ITT

Coombes, ASCO 2006.

IES Substudy ResultsIES Substudy Results

IES Quality of Life SubstudyIES Quality of Life Substudy

To compare and describe the quality of life (QOL) of women allocated to To compare and describe the quality of life (QOL) of women allocated to tamoxifen or exemestane within the IES tamoxifen or exemestane within the IES

Trial Outcome Index (TOI), which incorporates Trial Outcome Index (TOI), which incorporates PPhysical Well-Being,hysical Well-Being, Functional Functional Well-Being, and Breast Cancer Subscale Well-Being, and Breast Cancer Subscale

Total Functional Assessment of Total Functional Assessment of Cancer Therapy-Breast and Endocrine Cancer Therapy-Breast and Endocrine Subscale (Subscale (FACTFACT--B B ++ ES) scores ES) scores

Individual endocrine symptomsIndividual endocrine symptoms

Fallowfield, et al. J Clin Oncol. 2006;24:910-917.

RationaleRationaleRationaleRationale

Primary End PointPrimary End PointPrimary End PointPrimary End Point

Secondary End PointsSecondary End PointsSecondary End PointsSecondary End Points

IES Quality of Life Substudy MethodsIES Quality of Life Substudy Methods

• 582 consenting patients 582 consenting patients from 8 countriesfrom 8 countries

• 22 year year follow-up follow-up

• 3, 6, 9, and 12 months 3, 6, 9, and 12 months

• 6 monthly until 36 months6 monthly until 36 months

• Yearly until 60 months Yearly until 60 months

• 1-month post-recurrence1-month post-recurrence

SampleSampleSampleSample

AssessmentsAssessmentsAssessmentsAssessments

ResultsResultsResultsResults


IES Quality of Life Substudy OutcomesIES Quality of Life Substudy Outcomes


No significant differenceNo significant difference in QOL in QOL for for ttamoxifen and exemestane patientsamoxifen and exemestane patientsNo significant differenceNo significant difference in QOL in QOL for for ttamoxifen and exemestane patientsamoxifen and exemestane patients

BaselineBaseline 3 Months3 Months 6 Months 6 Months 9 Months 9 Months 12 Months 12 Months

Me

an

Ch

an

ge

Fro

m

Me

an

Ch

an

ge

Fro

m

Bas

eli

ne

Bas

eli

ne

-5-5

-4-4

-3-3

-2-2

-1-1

00

11

22

33

44

55

18 Months 18 Months 24 Months 24 Months


BaselineBaseline 3 Months3 Months 6 Months 6 Months 9 Months 9 Months 12 Months 12 Months

Me

an

Ch

an

ge

Fro

m

Me

an

Ch

an

ge

Fro

m

Bas

eli

ne

Bas

eli

ne

-5-5

-4-4

-3-3

-2-2

-1-1

00

11

22

33

44

55

18 Months 18 Months 24 Months 24 Months


Trial Outcome Index (TOI) Scores

Endocrine Subscale Scores

IES Quality of Life Substudy:IES Quality of Life Substudy:Endocrine SymptomsEndocrine Symptoms


Hot FlashesHot Flashes

Cold SweatsCold Sweats

Night SweatsNight Sweats

Sleeping Sleeping DifficultiesDifficulties

Vasomotor SymptomsVasomotor Symptoms Neuropsychological SymptomsNeuropsychological Symptoms

No difference between No difference between treatment groupstreatment groups


OROR E (%)E (%) T (%)T (%)

1.10 (0.78 to 1.54)1.10 (0.78 to 1.54)1.22 (0.72 to 2.05)1.22 (0.72 to 2.05)0.85 (0.58 to 1.25)0.85 (0.58 to 1.25)

1.12 (0.76 to 1.65) 1.12 (0.76 to 1.65)

46.046.019.419.432.232.234.634.6

44.744.718.418.434.834.834.534.5

.05.05 0.50.5 1.01.0 1.51.5 2.02.0 2.52.5 3.03.0

Odds Ratio (95% CI) – Log ScaleOdds Ratio (95% CI) – Log Scale

Favors Exemestane

Favors Tamoxifen

Lack of EnergyLack of Energy

Nervous FeelingNervous Feeling

HeadachesHeadaches

Feeling IrritableFeeling Irritable

OROR E (%)E (%) T (%)T (%)

1.17 (0.84 to 1.65)1.17 (0.84 to 1.65)0.93 (0.58 to 1.50)0.93 (0.58 to 1.50)0.69 (0.39 to 1.24)0.69 (0.39 to 1.24)1.38 (0.86 to 2.21)1.38 (0.86 to 2.21)1.02 (0.63 to 1.64)1.02 (0.63 to 1.64)

1.03 (0.57 to 1.86) 1.03 (0.57 to 1.86)

37.737.719.719.711.411.418.318.320.820.816.616.6

34.134.119.819.812.012.015.015.019.819.815.015.0

.05.05 0.50.5 1.01.0 1.51.5 2.02.0 2.52.5 3.03.0


Mood SwingsMood Swings

Light-Headed ‘Dizzy’Light-Headed ‘Dizzy’

Favors Exemestane

Favors Tamoxifen

IES Quality of Life Substudy:IES Quality of Life Substudy:Endocrine SymptomsEndocrine Symptoms


Bloated FeelingBloated Feeling

DiarrheaDiarrhea

Gastrointestinal SymptomsGastrointestinal Symptoms Gynecologic SymptomsGynecologic Symptoms


Vaginal discharge less frequent for Vaginal discharge less frequent for exemestane (exemestane (PP<0.001)<0.001)

No difference between treatment No difference between treatment groups for other GYN symptomsgroups for other GYN symptoms

NauseaNausea

Gained WeightGained Weight

OROR E (%)E (%) T (%)T (%)

1.21 (0.49 to 2.99)1.21 (0.49 to 2.99)0.96 (0.68 to 1.34)0.96 (0.68 to 1.34)0.75 (0.21 to 2.63)0.75 (0.21 to 2.63)0.87 (0.40 to 1.19)0.87 (0.40 to 1.19)

0.79 (0.52 to 1.19) 0.79 (0.52 to 1.19)

5.25.246.746.72.12.16.66.6

23.523.5

.05.05 0.50.5 1.01.0 1.51.52.02.0 2.52.5 3.03.0


VomitingVomiting

4.84.848.148.12.12.17.27.2

28.028.0

Vaginal DischargeVaginal Discharge

Discomfort IntercourseDiscomfort Intercourse

Lost Interest in SexLost Interest in Sex

Breast TendernessBreast Tenderness

Vaginal IrritationVaginal Irritation

OROR E (%)E (%) T (%)T (%)

0.25 (0.14 to 0.46)0.25 (0.14 to 0.46)0.65 (0.34 to 1.23)0.65 (0.34 to 1.23)0.29 (0.09 to 1.01)0.29 (0.09 to 1.01)1.14 (0.73 to 1.77)1.14 (0.73 to 1.77)0.96 (0.56 to 1.65)0.96 (0.56 to 1.65)1.03 (0.70 to 1.50)1.03 (0.70 to 1.50)

1.16 (0.73 to 1.87) 1.16 (0.73 to 1.87)

7.67.69.39.32.12.1

23.523.514.914.941.241.219.419.4

.05.05 0.50.5 1.01.0 1.51.5 2.02.0 2.52.5 3.03.0


17.117.112.612.63.43.4

26.326.315.015.045.445.422.522.5

Vaginal BleedingVaginal Bleeding

Vaginal DrynessVaginal Dryness

Favors Exemestane

Favors Tamoxifen

Favors Exemestane

Favors Tamoxifen

IES Endometrial SubprotocolIES Endometrial Subprotocol

Tamoxifen induces uterine abnormalities detectable in Tamoxifen induces uterine abnormalities detectable in postmenopausal women. postmenopausal women.

Does switching to exemestane impact the uterus?Does switching to exemestane impact the uterus?

Endometrial thickness Endometrial thickness ≥≥5 mm after 2 years of randomized 5 mm after 2 years of randomized treatmenttreatment

Transvaginal ultrasound changes, mean uterine volume, Transvaginal ultrasound changes, mean uterine volume, presence of polyps, fibroids, ovarian cystspresence of polyps, fibroids, ovarian cysts

Histologic and immunohistochemical findings in patients who Histologic and immunohistochemical findings in patients who undergo biopsy or hysterectomyundergo biopsy or hysterectomy




Bertelli, et al. SABCS. 2004.

IES Endometrial SubstudyIES Endometrial Substudy

-35%

-30%

-25%

-20%

-15%

-10%

-5%

0%

5%

10%

ExemestaneExemestanen=47n=47

TamoxifenTamoxifenn=43n=43

31.0%31.0%

5.3%5.3%

Ch

ang

e F

rom

Bas

elin

e (%

)C

han

ge

Fro

m B

asel

ine

(%)

Endometrial thickening was reversed to normal for Endometrial thickening was reversed to normal for 50% of patients treated with exemestane50% of patients treated with exemestane

Data on file, Pfizer Inc.

Median Change in Endometrial Thickness at 2 Median Change in Endometrial Thickness at 2 YYearsears

IES Bone SubstudyIES Bone Substudy

•• Tamoxifen may have bone-sparing properties Tamoxifen may have bone-sparing properties •• Bone loss has been established for AIsBone loss has been established for AIs•• Does switching to exemestane impact bone mineral density and bone Does switching to exemestane impact bone mineral density and bone

biomarkers? biomarkers?

• • Annual changes from baseline in lumbar spine and total hip bone Annual changes from baseline in lumbar spine and total hip bone mineral density (BMD)mineral density (BMD)

•• BMD between treatment groups at 12 and 24 months BMD between treatment groups at 12 and 24 months •• Changes in biochemical markers of bone turnoverChanges in biochemical markers of bone turnover•• Assess relationship between change in biochemical markers and BMDAssess relationship between change in biochemical markers and BMD•• Effects on fracture incidenceEffects on fracture incidence

Coleman, SABCS. 2005.




15

10

5

0

-5

-10

-15

IES Bone Substudy: Bone Mineral DensityIES Bone Substudy: Bone Mineral Density

Lumbar Spine

% C

ha

ng

e F

rom

Ba

se

lin

e 15

10

5

0

-5

-10

-15

TamoxifenExemestane

6 months

12 months

24 months

% C

ha

ng

e F

rom

Ba

se

lin

e

Total Hip

Coleman, SABCS. 2005.

-0.768-0.768

-2.887-2.887 -3.197-3.197 -3.642-3.642

-0.164-0.164 -0.178-0.178 -0.594-0.594

-1.577-1.577 -2.136-2.136 -2.398-2.3980.0000.000 -0.340-0.340

Exemestane Tamoxifen Patients enrolled, E=100, T=106.

IES Bone Substudy: Changes in Bone BiomarkersBone Biomarkers

ALP, alkaline phosphatase. Coleman, SABCS. 2005.

Exemestane (n=93)

0

5

10

15

0 3 6 9 12 18 24

DP

D/C

r (n

M/m

M)

Bone Resorption Bone Resorption

01020304050

0 3 6 9 12 18 24Time since randomization (months)

Bo

ne

AL

P (

U/L

) Bone Formation Bone Formation

Tamoxifen (n=103)

Normal range in healthy postmenopausal women

Exemestane (n=93)

Tamoxifen (n=102)

Independent Exemestane Independent Exemestane Cost-Effectiveness Studies Cost-Effectiveness Studies

Definition of Quality Adjusted Life Year Definition of Quality Adjusted Life Year

• Quality Adjusted Life Year (QALY)Quality Adjusted Life Year (QALY): A year of : A year of life adjusted for its quality. life adjusted for its quality.

• QALY exampleQALY example: : – A year in perfect health is considered equal to A year in perfect health is considered equal to

1.0 QALY1.0 QALY

– A year bedridden might have a value equal to A year bedridden might have a value equal to 0.5 QALY0.5 QALY

Source: www.medterms.com.

Overview of Cost-Effectiveness:Overview of Cost-Effectiveness:Exemestane Below Range Exemestane Below Range

CountryCountry AuthorAuthor US$/QALYUS$/QALY

Generally accepted rangeGenerally accepted range NANA $50,000 - $100,000 $50,000 - $100,000

BelgiumBelgium SkedgelSkedgel $18,156$18,156

USAUSA ThompsonThompson $15,300$15,300††

UKUK WordsworthWordsworth $12,809$12,809

CanadaCanada RisebroughRisebrough $15,516$15,516

*TAM-EXE versus TAM at 10 years; *TAM-EXE versus TAM at 10 years; ††ER-positive only patients.ER-positive only patients.QALY, Quality-adjusted life-year; based on DFS. QALY, Quality-adjusted life-year; based on DFS. Calculated in US dollars based on exchange rates as of May 31, 2006.

Skedgel, et al. EBCC. 2006; Thompson, et al. SABCS. 2005; Wordsworth, et al. EBCC. 2006; Risebrough, et al. SABCS. 2005.

PremenopausePremenopause

Role of Ovarian Ablation in Role of Ovarian Ablation in Absence of ChemotherapyAbsence of Chemotherapy

15-15-yearyear

DFSDFS

Risk Risk reductioreductio

nn

15-15-yearyear

OS*OS*

Risk Risk reductireducti

on*on*

OvxOvx 59.059.0%%

31% SE 31% SE 88

P=0.000P=0.0000606

59.459.4%%

31% SE 31% SE 77

P=0.00P=0.00003003

ContrControlol

45.645.6%%

49.149.1%%

Fifth Main Meeting of theEarly Breast Cancer Trialists’ Collaborative Group

Oxford, 21-23 September 2000

*Breast deaths inc. unk.

Goserelin vs Not: Goserelin vs Not: RecurrencesRecurrences

Chemotherapy versus LHRH Chemotherapy versus LHRH analogues in premenopausal analogues in premenopausal breast cancer patients breast cancer patients

TrialTrial PatientsPatients: : number number selectioselectionn

ChemotherChemotherapyapy

Follow-Follow-up up (years)(years)

ResultResult

ZEBRAZEBRA11

1640/1640/

ER±ER±CMF x 6CMF x 6

days 1 + 8days 1 + 855 NS for NS for

ER+ER+

TABLETABLE22 600/600/

ER+/ER+/PgR+PgR+

CMF x 6CMF x 6

days 1 + 8days 1 + 822 NSNS

1Eur J Cancer 2000; 36 (Suppl 5): S67; 2Proc ASCO 2001; 20: 34a

ZEBRA Trial

15-15-yearyear

DFSDFS


onon

15-15-yearyear

OS*OS*


on*on*

OvxOvx 52.552.5%%

7% SE 7% SE 77

P=nsP=ns

52.452.4%%

3% SE 73% SE 7

P=nsP=nsContrControlol

55.855.8%%

47.147.1%%

*Breast deaths inc. unk.

Fifth Main Meeting of theEarly Breast Cancer Trialists’ Collaborative Group

Oxford, 21-23 September 2000

Role of Ovarian Ablation Role of Ovarian Ablation in Presence of in Presence of Chemotherapy Chemotherapy

Incidence of Chemotherapy-Incidence of Chemotherapy-induced induced AmenorrheaAmenorrhea

RegimenRegimen CMF x 6-12CMF x 6-12 53-89%53-89% CEF x 6CEF x 6 61%61% ETET 40%40% ACAC 34%34% MFMF 9% 9%

AgeAge ≤ ≤ 40 years40 years 22-61%22-61% > 40 years> 40 years 61-97%61-97%

Role of Ovarian Ablation Role of Ovarian Ablation in Presence of in Presence of Chemotherapy Chemotherapy

StudyStudy StatStatusus

PtsPts OutcomeOutcome

Int-0101Int-0101

(3 arms)(3 arms)N+ N+ HR+HR+

15015044

G+CAF=CAFG+CAF=CAF

IBCSG IBCSG 11-11-9393

N+ N+

HR+HR+174174 G+TG+T==G+T+ACG+T+AC

IBCSG IBCSG VIIIVIII

(3 arms)(3 arms)

N-N-

ER+/ER+/--

10610633

ER+ ER+ GG+CMF=CMF+CMF=CMF

Adjuvant AI after Adjuvant AI after chemotherapy induced chemotherapy induced amenorrhoea : results from amenorrhoea : results from an auditan audit

IE Smith, J Clin Oncol 2006

45 patients (39-52 years)

12 showed a return of ovarian function

(10 renewed menses, 1 biochemically premenopausal and 1 pregnancy)

Adjuvant AI after Adjuvant AI after chemotherapy induced chemotherapy induced amenorrhoea amenorrhoea Most women older than age 40 treated with Most women older than age 40 treated with

CT will develop permanent amenorrhoeaCT will develop permanent amenorrhoea But in a minority amenorrhoea may be But in a minority amenorrhoea may be

temporary (0-11%)temporary (0-11%) The incidence of recovery may be The incidence of recovery may be

increased by AIs (27% in the report by increased by AIs (27% in the report by Smith)Smith)

Predicting which pts will have return of Predicting which pts will have return of ovarian function is not possible (a single ovarian function is not possible (a single measurement of FSH, LH and E2 reflects measurement of FSH, LH and E2 reflects function only that time point)function only that time point)

Aromatase Aromatase Inhibitors Inhibitors Adjuvant TrialsAdjuvant Trials

AI Adjuvant AI Adjuvant Trials. Trials. Disease Free SurvivalDisease Free Survival

StudyStudy n. n. ptspts

FUFU

YrsYrs

DFS – HRDFS – HR

(95% CI)(95% CI)Abs. Abs. Diff.Diff.

ATACATAC Lancet 05Lancet 05 93693666

5.75.7 0.87 0.87 (0.78-(0.78-0.97)0.97)

2.8%2.8%

BIG1-98BIG1-98 NEJM 05NEJM 05 80180100

2.22.2 0.81 0.81 (0.70-(0.70-0.93)0.93)

2.6%2.6%

IESIES NEJM 04NEJM 04 47447422

2.72.7 0.68 0.68 (0.56-(0.56-0.82)0.82)

4.7%4.7%

ARNO/ABCSGARNO/ABCSG Lancet 05Lancet 05

32232244

2.32.3 0.60 0.60 (0.44-(0.44-0.81)0.81)

3.1%3.1%

ITAITA JCO 05JCO 05 448448 3.03.0 0.35 0.35 (0.18-(0.18-0.68)0.68)

5.3%5.3%

MA 17MA 17 JNCI 05JNCI 05 51851877

2.52.5 0.58 0.58 (0.45-(0.45-0.76)0.76)

4.6%4.6%

Receptors Profile & Treatment Receptors Profile & Treatment SelectionSelection

Hormonotherapy + Hormonotherapy + ChemotherapyChemotherapy

Tamoxifen and/or Aromatase Tamoxifen and/or Aromatase InhibitorsInhibitors

Receptors Profile & Treatment Receptors Profile & Treatment SelectionSelection

Hormonotherapy + ChemotherapyHormonotherapy + Chemotherapy Tamoxifen and/or Aromatase Tamoxifen and/or Aromatase

InhibitorsInhibitors

CLINICAL CASE 1: CLINICAL CASE 1: ADJUVANT ENDOCRINE THERAPYADJUVANT ENDOCRINE THERAPY

55-year old, 55-year old, postmenopausalpostmenopausalinv. ductal Cainv. ductal Ca

RiskRisk : : sentinel node –sentinel node –

Size = 1.1cmSize = 1.1cmGrade 1Grade 1

ResponsivenessResponsiveness : : ER 8/8, PgR 8/8ER 8/8, PgR 8/8HER2 negativeHER2 negative

Grade 1Grade 1

St.Gallenexperts

Otherexperts

Youngexperts

TAM x 5y

TAM x 5yAI

ANYAITAM x 2-3yAI

M. Piccart, SABCS 2005

Adjuvant Aromatase Adjuvant Aromatase InhibitorsInhibitors

StudyStudy therapytherapy f.u.f.u. HRHR Abs dAbs d

ATAC 03ATAC 03 upfrontupfront 44 0.820.82 3%3%

ITA 04ITA 04 switchswitch 33 0.360.36 5.3%5.3%

IES 04IES 04 switchswitch 2.72.7 0.680.68 4.7%4.7%

MA17 04MA17 04 extendedextended 2.52.5 0.580.58 5 %5 %

ARNO -ARNO -ABCSG 04 ABCSG 04

switchswitch 0.60.6 3%3%

BIG 05BIG 05 upfrontupfront 2.42.4 0.810.81 2.6%2.6%



















Primarysurgery

R a

n d

o m

I z a

t I o n

Tamoxifen (5 years) to start within 6 weeks of surgery

Tamoxifen (2 years)

Anastrozole (3 years)

Switching period

Sequencing period

ABCSG 8 trial structureABCSG 8 trial structure

ABCSG Trial 8 analysisABCSG Trial 8 analysis3901 patients screened

180 patients not meeting entry criteria

2926 patients eligible for the sequencing analysis

795 patients with a switch date after presentation of the ABCSG / ARNO

combined analyses (SABCS 2004) & the IDMC recommendation to stop the trial

1472 patients randomized to receive 2 years’ tamoxifen then 3 years‘ anastrozole

1454 patients randomized to receive 5 years’ tamoxifen

2529 patients eligible for the switching analysis

397 patients had a BC specific event, a secondary carcinoma, died or withdrew

during the initial 2-year tamoxifen period

Event-free survival following surgery: Event-free survival following surgery: ABCSG 8ABCSG 8(n = 2926)(n = 2926)

0

75

80

85

90

95

100

0 12 24 36 48 60 72

Time since surgery (months)

EFS(%)

Therapy switch

TA

29Events

HR

p-value

T

24

1.19

0.519

First 2 years

98.3%

98.0%TAT


0

75

80

85

90

95

100

0 12 24 36 48 60 72


EFS(%)

Therapy switch

Events

HR

p-value

T

77

0.63

0.010

A

50

After switch

TAT


0

75

80

85

90

95

100

0 12 24 36 48 60 72


EFS(%)

HR

0.76Events

p-value

0.068

T

101

TA

79

94.4%

92.9%

TAT

CLINICAL CASE 1: CLINICAL CASE 1: ADJUVANT ENDOCRINE THERAPYADJUVANT ENDOCRINE THERAPY

55-year old, 55-year old, postmenopausalpostmenopausalinv. ductal Cainv. ductal Ca

RiskRisk : : sentinel node –sentinel node –

Size = 1.1cmSize = 1.1cmGrade 1Grade 1

ResponsivenessResponsiveness : : ER 8/8, PgR 8/8ER 8/8, PgR 8/8HER2 negativeHER2 negative

Grade 1Grade 1 12%12% 12%12%

47%47%

17%17%11%11%

11%11%

16%16%

26%26%

20%20%

33%33%

32%32%

5%5%

25%25%

32%32%

0%0%

St.Gallenexperts

Otherexperts

Youngexperts

TAM x 5y

TAM x 5yAI

ANYAITAM x 2-3yAI

M. Piccart, SABCS 2005

Recurrence Hazard Rates for Breast Cancer After Primary Therapy

Saphner et al. J Clin Oncol 1996;14:2738-2746.

Patients (%)

Follow-up time (years)

20

25HR

0.74HR+

95% CI

(0.64–0.87)

p-value

0.0002

A

282

T

370

At risk:A 2618 2540 2448 2355 2268 2014 830T 2598 2516 2398 2304 2189 1932 774

ATAC: recurrences* before 2.5 ATAC: recurrences* before 2.5 years years (HR+ patients)(HR+ patients)

* Censoring non-BC deaths before recurrence

0

5

10

15

0 1 2 3 4 5 6

‘Arimidex’ (A)Tamoxifen (T)

BIG 1-98: cumulative incidence of BIG 1-98: cumulative incidence of breast cancer relapsebreast cancer relapse

Proportionfailing(%)

Time since randomisation (years)

5-year difference (L-T) = -3.4% (SE 1.2)Cuminc p=0.0002

0 1 2 3 4 5

0

5

10

15

20

13.6%

10.2%

6.2%

8.1%

Letrozole (L)

Tamoxifen (T)

SE = standard error

Thürlimann B et al. The Breast 2005;14:S3, abs S4

%RFS

100

80

0 1 2 3 4 5

years

90

70

100

6 7 7.5

%RFS

100

80

0 1 2 3 4 5

years

90

70

100

6 7 7.5

HR Profile : prognosis and hormone-resistance

ER+/PR- breast cancer: biologic characteristics

ER+/PR- ER+/PR+ P value

No. Pts 31403 13399

Median level of ER (fmol/mg)

(Range)

47

(3-2211)

103

(3-3290)

<.001

HER1 expression* 25% 8% <.001

HER2 overexpression* 21% 14% <.001

* no. Patients: 1306 and 634. Arpino et al. JNCI 2005

Response by PgR Allred expression category

0

10

20

30

40

50

60

70

80

90

0 2 3 4 5 6 7 8

tamoxifenletrozole

Allred PgR Score

Res

pons

e ra

te

25.4 6.2 8.0 11.2 8.0 14.1 8.7 18.5

% of cases in each category

Copyright © American Society of Clinical Oncology

Bardou, V.-J. et al. J Clin Oncol; 21:1973-1979 2003

Fig 1. (A) Disease-free survival and (B) overall survival according to estrogen receptor/progesterone receptor status, in the first database Program Project

patients who received no systemic adjuvant therapy

Copyright © American Society of Clinical Oncology

Bardou, V.-J. et al. J Clin Oncol; 21:1973-1979 2003

Fig 3. Overall survival according to estrogen receptor/progesterone receptor status in the second database Specialized Program of Research Excellence

patients who received systemic endocrine therapy

Copyright restrictions may apply.

Dowsett, M. et al. Ann Oncol 2006 17:818-826; doi:10.1093/annonc/mdl016

Relapse free survival for the patients available for biomarker analysis from the NATO and CRC adjuvant trials

Tovey S. et al, Clin Cancer Res 2005

Factors predicting resistance to Tamoxifen



Relapse free survival according to PgR status

HER-2 in HR+: prognosis and hormone-resistance

Tovey S. et al, Clin Cancer Res 2005

Factors predicting resistance to Tamoxifen


Arpino, G. et al. J Natl Cancer Inst 2005;97:1254-1261

Kaplan-Meier curves for disease-free survival in tamoxifen-treated patients

ER+/PR+ ER+/PR-

Dowset M, SABCS 2003A

BIG 1-98 DFS by Central Pathological Assessment

Favors L Favors T

1.00.5 0.75 1.25 1.5

Hazard Ratio (L:T)

ER+ / HER2+ (n=234)

ER+ / HER2- (n=3971)

0.68

0.72

All patients (n=4399)0.71

IES : subgroups

RC Coombes SABCS 2004



Relative risk of relapse according to HER2 positivity in steroid receptor positive subgroup

SafetySafety

Effects of estrogens in Effects of estrogens in different organ systemsdifferent organ systems

Influence on moodInfluence on mood NeuroprotectionNeuroprotection Reduction of intraocular pressureReduction of intraocular pressure Amelioration of skin agingAmelioration of skin aging Maintenance of Bone DensityMaintenance of Bone Density Arterial VasodilationArterial Vasodilation CardioprotectionCardioprotection Growth and proliferation of breast tissue; risk factors Growth and proliferation of breast tissue; risk factors

for breast cancerfor breast cancer Increase production livel proteins such as coagulation Increase production livel proteins such as coagulation

factors and hepatic lipoprotein receptorsfactors and hepatic lipoprotein receptors Putative reduction in risk of colon cancerPutative reduction in risk of colon cancer Growth and differentiation of and water retention in Growth and differentiation of and water retention in

primary sex organs; risk factor for endometrial cancerprimary sex organs; risk factor for endometrial cancer

CJ Gruber, NEJM 2002

Cognitive Function in HRT Cognitive Function in HRT trialstrials

During a mean follow-up of 5.4 years During a mean follow-up of 5.4 years 3MSE scores were lower for ERT 3MSE scores were lower for ERT than for placebo (risk of having a 10 than for placebo (risk of having a 10 unit decrease in 3MSE scores = 1.47)unit decrease in 3MSE scores = 1.47)

Pooled data of ERT and ERPT show Pooled data of ERT and ERPT show an increase risk for dementia and an increase risk for dementia and Mild Cognitive ImpairmentMild Cognitive Impairment

M Espeland, JAMA 2004

S Shumaker, JAMA 2004


Fisher, B. et al. J Natl Cancer Inst 2005;97:1652-1662

Comparison of relative risks (with 95% confidence intervals) of benefits and undesirable effects of tamoxifen from the initial and updated results of NSABP P-1

AIs versus Placebo:AIs versus Placebo:Letrozole in Tam pretreated Letrozole in Tam pretreated patientspatients

Letrozole vs Placebo (MA-Letrozole vs Placebo (MA-17)17)

90% of AEs grade 1 or 2.

Letrozole Letrozole PlaceboPlacebo PP Value Value

Hot flashesHot flashes 5858 5454 0.0030.003

Arthritis/arthralgiaArthritis/arthralgia 2525 2121 < 0.0001< 0.0001

Muscle painMuscle pain 1515 1212 0.040.04

Vaginal bleedingVaginal bleeding 66 88 0.0050.005

HypercholesterolemiaHypercholesterolemia 1616 1616 0.790.79

Cardiovascular eventsCardiovascular events 66 66 0.760.76

OsteoporosisOsteoporosis 88 66 0.0030.003

Discontinuations due to adverse eventDiscontinuations due to adverse event 55 44 0.020.02

Discontinuations due to other reasonsDiscontinuations due to other reasons 44 55 0.10.1

% of Patients

Adapted from Goss. ASCO, 2004.













% of Patients














% of Patients


Cholesterol levels in MA.17Cholesterol levels in MA.17

MA.17 MA.17

(30 mos FU)(30 mos FU)LET LET

(n=2575)(n=2575)Placebo Placebo

(n=2582)(n=2582)

HypercholesterolemiHypercholesterolemiaa

(all grades)(all grades)

16%16% 16%16%

Goss et al. Proc ASCO 2004;23:87(Abstract 847)

Letrozole did not adversely affect lipid levels compared with placebo (p = 0.79) in whole study population

MA.17L HDL:LDL ratio MA.17L HDL:LDL ratio throughout study periodthroughout study period


0,47 0,47 0,490,47 0,48

0,58

0,45

0,55

0

0,2

0,4

0,6

0,8

Month 0 Month 6 Month 12 Month 24

Letrozole

Placebo

HD

L:L

DL

rat

io

*p values refer to change from baseline

p = 0.282* p = 0.351 p = 0.962

MA.17: Ischemic cardiovascular MA.17: Ischemic cardiovascular diseasedisease


Compared with placebo, letrozole had no detrimental effect Compared with placebo, letrozole had no detrimental effect on CV disease in >5000 patientson CV disease in >5000 patients

144 (5.6%)144 (5.6%)149 (5.8%)149 (5.8%)CV disease, all gradesCV disease, all grades

Placebo Placebo (n = 2582)(n = 2582)

LetrozoleLetrozole(n = 2575)(n = 2575)

MA.17 MA.17 (30 mo FU)(30 mo FU)22













% of Patients


MA.17 Safety profile: Bone MA.17 Safety profile: Bone

* Patient-reported

137

209

119

155

0

50

100

150

200

New osteoporosis* Fractures

Letrozole

Placebo

No

. of

pa

tie

nts

(p = 0.25)

(p = 0.003)

(8%)

(5.3%)

(6%)

(4.6%)

Adapted from Goss. ASCO, 2004

AIs versus AIs versus Placebo:Placebo:ExemestaneExemestane

Exemestane vs placebo: Exemestane vs placebo: BMD & lipids resultsBMD & lipids results

Annual rate of BMD loss was significantly p Annual rate of BMD loss was significantly p <0.05) higher in the femoral neck and not in <0.05) higher in the femoral neck and not in the lumbar spinethe lumbar spine

Increase of bone resorption and formation Increase of bone resorption and formation markers; return to baseline within 6 monthsmarkers; return to baseline within 6 months

Modest reduction of HDL-cholelesterol Modest reduction of HDL-cholelesterol (p<0.001) and Apolipoprotein A1 (p= 0.004)(p<0.001) and Apolipoprotein A1 (p= 0.004)

No effect on other lipid parameters, No effect on other lipid parameters, homocysteine levels or coagulation homocysteine levels or coagulation parametersparameters

P Lonning, JCO 2005 & ASCO 2005

AIs versus AIs versus TamoxifenTamoxifen

Arthritis/Arthritis/ArthralgiasArthralgias

Joint SymptomsJoint SymptomsArthralgiArthralgiaa

ArthritiArthritiss

ArthrosArthrosisis

Joint Joint disorderdisorder

AnastrozoAnastrozolele

15.1%15.1% 16.6%16.6% 6.7%6.7% 6.0%6.0%

TamoxifeTamoxifenn

11.1%11.1% 14.4%14.4% 5.0%5.0% 5.2%5.2%

50% recovered in 6 months and 75% recovered in 18 months

60% received treatment (>90% NSAI)

2% with Ana and 0.9% with Tam withdrew

AU Buzdar, ASCO 2006

Gynecological Gynecological ProblemsProblems

Gynecological issues with Gynecological issues with TamTam

Higher incidence of endometrial cancerHigher incidence of endometrial cancer Related to duration (OR 1.9 for 2-4 years of Related to duration (OR 1.9 for 2-4 years of

Tam)Tam) Related to “time since last use known”Related to “time since last use known”

Poorer prognosis endometrial cancer?Poorer prognosis endometrial cancer? Higher incidence of vaginal bleedingHigher incidence of vaginal bleeding Greater endometrial thickness (lower Greater endometrial thickness (lower

sensitivity, specificity and PPV)sensitivity, specificity and PPV)

Swerdlow, JNCI 2005;Bergman, Lancet 2000; Duffy, Human Reprod 2005

““Endometrial events” :Endometrial events” :Tamoxifen vs Aromatase Tamoxifen vs Aromatase InhibitorInhibitor

HysterectoHysterectomymy

EndometriEndometrialal

biopsiesbiopsies

ATACATAC 5% vs 1%5% vs 1%

BIG 1BIG 1 7.2% vs 7.2% vs 1.9%1.9%

Effect of AIs Effect of AIs on the lipid on the lipid profileprofile

Hypercholesterolemia Hypercholesterolemia reported in adjuvant AI reported in adjuvant AI trialstrials

Refs.: ATAC Trialists’ Group Lancet 2005;356:60–2, Thürlimann et al. www.ibscg.org, Coombes et al. N Engl J Med 2004;350:1081–92, Boccardo et al Clin Breast Cancer 2004;5:S13–7;Goss et al. N Engl J Med 2003;349:1793–802.

* Not systematically collected

Study FU(MO) AI Ref. Drug Event AI vs Ref. (%) p

ATAC BIG 1-98

60

26

Anastrozole

Letrozole

Tamoxifen

Tamoxifen

All grades Grade I

6.8 vs 2.6*

43.5 vs 19.1 38.1 vs 17.3

NI NI

IES

ITA

31

52

Exemestane

Anastrazole

Tamoxifen

Tamoxifen

Not reported

8 vs 3

0.01

Serum cholesterol levels in Serum cholesterol levels in BIG 1-98BIG 1-98Median change (%) versus Median change (%) versus baselinebaseline

Letrozole Tamoxifen

6 months N 2234 2201 Median 0% -12.1% 12 months N 2230 2201 Median 0% -13.6% 24 months N 1818 1810 Median -1.9% -14.7% 36 months N 933 914 Median -6.6% -9.2% 48 months N 461 474 Median -5.4% -13.5% 60 months N 290 266 Median -2.1% -15.4% Source: Appendix 8, Table 10-3k

Tamoxifen & LipidsTamoxifen & Lipids

Review by Herrington of the effects of SERMs (2001) :Tamoxifen, raloxifen, droloxifenEffect on lipids (cholesterol, HDL, LDL, triglycerides, Lp(a), Apo A-I, Apo-BCoagulationEndothelial cells

Effect of tamoxifen:10 studies (6 against placebo), n = 644

Decrease of cholesterol seen in all studiesMedian decrease: 12.5% (range 3-17%)Decrease is due to LDL cholesterol

Effect of AIs on Effect of AIs on CVDCVD

Summary: Incidence of CVD Summary: Incidence of CVD in adjuvant AI trialsin adjuvant AI trials

ATAC Trialists’ Group Lancet 2005;365:60; Thürlimann et al. www.ibcsg.org. Coombes et al. N Engl J Med 2004;350:1081; Coombes et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 3); Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. Proc ASCO 2004;23:87(Abstract 847).

Study FU(mo) AI Ref. Drug Event AI vs Ref. (%) p

ATAC

BIG 1-98

60

26

Anastrozole

Letrozole

Tamoxifen

Tamoxifen Cardiac (All grades)Cardiac (Grade III–IV)

64.1 vs 3.4

4.1 vs 3.82.1 vs 1.1

NI

NI

IES

ARNO

31

28

Exemestane

Anastrazole

Tamoxifen

Tamoxifen

CVD

Not reported

MA.17 30 Letrozole Placebo 5.8 vs 5.6 0.67

Ischemic CVD 0.1Cardiac death Not reported

CVA/TIA

42.6 vs 39.2 0.2837 MI (All)

MI (on treatment)Cardiac deathVascular death

Ischemic CVD

Cardiac death 0.47 vs 0.78 NI

1.0 vs 1.00.0003

0.9 vs 0.40.7 vs 0.3

0.55 vs 0.500.63 vs 0.29

0.0230.126

NINI

BIG 1-98: Cardiovascular BIG 1-98: Cardiovascular events events (Grade 3–5)(Grade 3–5)

LetrozolLetrozolee

TamoxifTamoxifenen

pp

PatientsPatients 39753975 39883988

CVA/TIA gr 3–5CVA/TIA gr 3–5 1.0%1.0% 1.0%1.0% 1.01.0

Thromboembolic gr 3–5Thromboembolic gr 3–5 0.8%0.8% 2.1%2.1% < 0.0001< 0.0001

Cardiac gr 3–5Cardiac gr 3–5 2.1%2.1% 1.1%1.1% 0.00030.0003

Ischemic heart disease gr Ischemic heart disease gr 3–53–5

1.1%1.1% 0.6%0.6% 0.0130.013

Cardiac failure gr 3–5Cardiac failure gr 3–5 0.5%0.5% 0.1%0.1% 0.0060.006

Thürlimann et al. www.ibcsg.org;

Cardio-protective effect of Cardio-protective effect of tamoxifen tamoxifen MetanalysisMetanalysis

32 trials comparing tamoxifen against a control 32 trials comparing tamoxifen against a control group (metastatic, adjuvant, and prevention group (metastatic, adjuvant, and prevention settings) settings) 12 reported on myocardial infarction death12 reported on myocardial infarction death

> 52,000 patients; 66% postmenopausal; mean > 52,000 patients; 66% postmenopausal; mean age 54.8 yrs; mean treatment duration: 4.3 yrs; age 54.8 yrs; mean treatment duration: 4.3 yrs; mean FU: 5.6 yrsmean FU: 5.6 yrs

Relative risk ratio for fatal MIs (tamoxifen / Relative risk ratio for fatal MIs (tamoxifen / control): 0.62 (95% CI: 0.41-0.93)control): 0.62 (95% CI: 0.41-0.93)

Risk ratio without the Scottish trial: 0.81 (95% Risk ratio without the Scottish trial: 0.81 (95% CI: 0.48-1.37)CI: 0.48-1.37)

Braithwaite et al JGIM 2003;18:937-47

Cardio-protective effect of Cardio-protective effect of tamoxifentamoxifen

Early Breast Cancer Trialists Collaborative Early Breast Cancer Trialists Collaborative Group experience at 15 yrs (Lancet 2005)Group experience at 15 yrs (Lancet 2005)

~ 66,000 women treated with tamoxifen~ 66,000 women treated with tamoxifen Subset of ~15,000 women treated with 5 Subset of ~15,000 women treated with 5

yrs tamoxifen versus control:yrs tamoxifen versus control: 189 vs 169 vascular deaths (tamoxifen vs 189 vs 169 vascular deaths (tamoxifen vs

control, NS)control, NS) Stroke: 54 vs 29 (p=0.07)Stroke: 54 vs 29 (p=0.07) Thromboembolic: 15 vs 8 (NS); Thromboembolic: 15 vs 8 (NS); Cardiac cause: 120 vs 132 (p=0.06) Cardiac cause: 120 vs 132 (p=0.06)

Bone HealthBone Health

AI and fracturesAI and fractures

StudyStudy RxRx % % fracturesfractures

OROR P valueP value

ATACATACLancet 05Lancet 05

TamTam

AnaAna7.77.7

11111.491.49 <.0001<.0001

BIG 1-98BIG 1-98St. Gallen 05St. Gallen 05

TamTam

LetLet4.14.1

5.85.81.441.44 .0006.0006

IESIESASCO 06ASCO 06

TamTam

ExeExe7.07.0

4.94.9nrnr <.01<.01

Tam and fractures (NSABP-P1, JNCI 1998)

Pts > 50 yrs (tam vs placebo) HR: 0.79 (95% CI 0.60-1.05)

AT

30923094

29232932

27242741

25532579

23932401

20702100

845846

0.0

0.5

1.0

1.5

2.0

2.5

3.0

1 2 3 4 5 6


0

Anastrozole (A)

Tamoxifen (T)

At risk:

Annual rates(%)

Fracture risk over time: Fracture risk over time: ATACATAC

A Howell, ASCO 2006

AT

30923094

29232932

27242741

25532579

23932401

20702100

845846

0.0

0.5

1.0

1.5

2.0

2.5

3.0

1 2 3 4 5 6


0

Anastrozole (A)

Tamoxifen (T)

At risk:

Annual rates(%)

Fracture risk over time: Fracture risk over time: ATACATAC

Not only Anastrozole but also age, geographical region as risk factors; lower risk for concomitant statin.

A Howell, ASCO 2006

ATAC bone-substudyATAC bone-substudy

No pt with normal bone became No pt with normal bone became osteoporoticosteoporotic

Slowing down of bone-loss in years Slowing down of bone-loss in years 2-52-5

Correlation of bone markers and Correlation of bone markers and BMD decreaseBMD decrease

Patients at risk of bone loss should Patients at risk of bone loss should be identified and managedbe identified and managed

RE Coleman, ASCO 2006

Quality of LifeQuality of Life

Quality of Life - StudiesQuality of Life - Studies

TrialTrial SamplSample Sizee Size

InstrumeInstrumentnt

OutcomesOutcomes

ATACATAC 10211021 FACT-BFACT-B

Endocrine Endocrine subscalesubscale

No difference in No difference in overall HRLQOL or overall HRLQOL or endocrine subscaleendocrine subscale

IESIES 582582 FACT-BFACT-B

Endocrine Endocrine subscalesubscale

No difference in No difference in overall HRLQOL or overall HRLQOL or endocrine subscaleendocrine subscale

Quality of Life - StudiesQuality of Life - StudiesCOLD COLD SWEATSWEATSS

VAGINAL VAGINAL DISCHARGDISCHARGEE

IRRITATIOIRRITATIONN

VAGINAL VAGINAL DRYNESSDRYNESS

PAIN ON PAIN ON INTERCOURSINTERCOURSEE

LOSS OF LOSS OF SEXUAL SEXUAL INTERESTINTEREST

ANAANA 8%8% 1%1% 3%3% 16%16% 18%18% 16%16%

TAMTAM 11%11% 5%5% 5%5% 8%8% 8%8% 9%9%

pp <0.05<0.05 <0.05<0.05 <0.05<0.05 <0.05<0.05 <0.05<0.05 <0.05<0.05

Quality of Life - StudiesQuality of Life - StudiesCOLD COLD SWEATSWEATSS

VAGINAL VAGINAL DISCHARGDISCHARGEE

IRRITATIOIRRITATIONN

VAGINAL VAGINAL DRYNESSDRYNESS

PAIN ON PAIN ON INTERCOURSINTERCOURSEE

LOSS OF LOSS OF SEXUAL SEXUAL INTERESTINTEREST

ANAANA 8%8% 1%1% 3%3% 16%16% 18%18% 16%16%

TAMTAM 11%11% 5%5% 5%5% 8%8% 8%8% 9%9%

pp <0.05<0.05 <0.05<0.05 <0.05<0.05 <0.05<0.05 <0.05<0.05 <0.05<0.05

Counteracting Counteracting the AIs the AIs negative negative effectseffects

ASCO GuidelinesASCO Guidelines

BMD T –score >-1BMD T –score between

-1 and -2.5BMD T –score ≤-2.5

Provide lifestyle advice including calcium and vitamin D

Provide ReassuranceConsider drug therapy

on an individualized basis

Begin drug therapy-Alendronate-Risendronate-Zoledronate-Raloxifene*

Patient base selection (not Patient base selection (not tumor profile): Tamoxifen to be tumor profile): Tamoxifen to be excludedexcluded

Tam res tumors (ER+PgR-, HER2+, Tam res tumors (ER+PgR-, HER2+, DVT riskDVT risk High metabolizersHigh metabolizers ……..

Selection on the basis of patient Selection on the basis of patient (not tumor profile): Tamoxifen to (not tumor profile): Tamoxifen to be excludedbe excluded

Pre (peri) menopausePre (peri) menopause Osteoporosis??Osteoporosis?? ……..

ConclusionsConclusions

ConclusionsConclusions

Pts at risk of breast cancer relapse and death Pts at risk of breast cancer relapse and death should receive the agent should receive the agent most effectivemost effective and and with the with the most manageable toxicitymost manageable toxicity

Tamoxifen cannot be considered for Tamoxifen cannot be considered for prevention or treatment of diseases of prevention or treatment of diseases of ageing womenageing women For osteopenia/osteoporosis: For osteopenia/osteoporosis: diet, physical diet, physical

activity, bisphosphonatesactivity, bisphosphonates For hypercholesterolemia: For hypercholesterolemia: diet, physical diet, physical

activity, statinsactivity, statins

Relative and absolute risk Relative and absolute risk reductionreduction

Intervention produces a 35% relative risk reduction

Node-negative Node-positive

20%13%

65%

42%

Initial risk

Final risk

Initial risk

Final risk

Difference: 7% 23%




20%13%

65%

42%

Initial risk

Final risk

Initial risk

Final risk

Difference: 7% 23%

- 5%




20%13%

65%

42%

Initial risk

Final risk

Initial risk

Final risk

Difference: 7% 23%NNT 14.2

NNT 4.3

Documents

A turning point in adjuvant therapy: Optimizing use of aromatase inhibitors P Pronzato Genova